The predominant role of the lens of the human eye is to focus light rays that have passed through the cornea and aqueous humour onto the retina. The structure and metabolism of the lens contributes directly toward maintaining its integrity and transparency. The lens is composed entirely of epithelial cells in different stages of maturation and is relatively unusual in that tissue is never discarded during the maturation process. As new lens cells are formed, older cells are displaced toward the interior of the lens. The lens soon becomes isolated from a direct blood supply and depends on the aqueous and vitreous humors for both nutrition and elimination pathways. The optical characteristics of the lens are much dependent on lens cells maintaining a constant cell volume and dense packing of the fibers to reduce the volume of intercellular space. Maintaining its delicate structure therefore becomes an essential characteristic of the lens. The lens has evolved its unique capabilities to maintain constant cell volume by regulating its ion, sugar, amino acid, and water balances.
A cataract of the human eye is the interruption of the transmission of light by loss of lens transparency. Cataracts, which cause blurring and clouding of vision, are by far the most common cause of low visual acuity. The clouded lens can be removed by surgical procedure, i.e. extra-capsular cataract extraction (ECCE). ECCE comprises the removal of the clinical nucleus with cortical cleanup using either manual or automated vacuuming techniques. The posterior and equatorial capsule is left intact as an envelope or bag into which a posterior chamber intraocular lens can be inserted. If the posterior capsule and zonules are intact, this lens will ordinarily remain in place throughout the patient's life without any complications. During the operation, the anterior portion of the lens capsule is carefully opened and the cataract is removed. The intraocular lens is inserted into the remaining (posterior) portion of the capsule. This also results partially in a loss of natural lens accommodation.
Standard cataract surgery employs a procedure known as phaco-emulsification. This process agitates the lens content causing break-up of the lens material, which is then sluiced out of the lens capsule by the phaco-emulsification probe that simultaneously injects and extracts a washing solution. Both dead and live lens epithelial cells detached by the treatment will be washed out by this sluicing action.
Progress is being made in the development of new treatments that involve retention of the anterior lens capsule and the replacement of the lens content with injectable material.
After this surgery, vision is restored but one of the most frequent complications of prevailing cataract surgery is the proliferation of lens epithelial cells (LECs) after cataract surgery. Posterior Capsular Opacification (PCO), also known as secondary cataract, is the most frequent complication following extra-capsular surgery, occurring in about twenty to forty percent of patients. In the past decade, results from a number of experimental and clinical studies have led to a better understanding of the pathogenesis of PCO.
The main cause of PCO is the proliferation and migration of residual LECs to the posterior lens capsule. Despite the care taken by surgeons to remove most of the residual lens epithelial cells, they are difficult to remove. Many LECs are, therefore, left behind in the lens capsular bag at the end of the surgical procedure. The proliferation of the LECs causes the membrane or envelope into which the intraocular lens is placed to become cloudy over time. Proliferation of LECs is also a significant problem in the new cataract treatments utilizing, for example, injectable lenses. The cloudy membrane is called an “after cataract” or PCO. The symptoms of PCO are identical to those of cataract, causing vision to gradually fade and eventually leading to blindness if not treated.
Much effort has been made to prevent or minimize formation of PCO. These efforts can be broadly categorized into three areas: surgical improvement, lens design improvement and chemical prevention.
A number of surgical strategies have been developed to attempt prevention of PCO. These have involved the use of various surgical instruments and the application of laser, ultrasound, and freezing techniques. Once PCO has occurred, YAG laser capsulotomy is a simple, quick procedure in which a laser beam is used to create an opening in the center of the cloudy capsule. There are, however severe risks associated with YAG laser capsulotomy. These mainly include the development of retinal detachment, glaucoma, cystoid macula oedema.
Much interest has centered on the type of material from which the intraocular lens is made and the profile of the intraocular lens' edge. Biconvex and planer convex polymethylacrylate as well as silicone plate hepatic intraocular lenses and lenses with sharp optic edges are reported to have a beneficial effect on PCO. Significant advances have been made in this area particularly by Alcon's Acrysof lens. These lenses are however relatively expensive and introduce complications or constraints of their own.
There have been other attempts to destroy or prevent proliferation of LECs making use of chemical agents. In British Patent Application 0122807.1, filed on Sep. 21, 2001, the hypothesis was that by decreasing intracellular sorbitol concentration in LECs by modulating sorbitol pathways via an aldose reductase inhibitor, PCO could be prevented by inducing death of LECs by osmotic shock. However, in order to modulate the sorbitol pathways, the proposed treatment involved pretreating the lens capsular bag for a period of up to 48 hours prior to surgery and is, therefore, not easily incorporated into current cataract surgery.
Other chemical therapies have been attempted. For example, the use of immunotoxin-conjugated antibody specific for LECs can reduce but not completely prevent the incidence of PCO. See Clark et al, J. Cataract Refract. Surg. 1998 December; 24(12): 1614-20 and Meacock et al, J. Cataract Refract. Surg. 2000 May; 26(5): 716-21. The use of ethylenediamine tetraacetic acid, Trypsin and DISPASE® (Neutral Protease) has also been used to separate the LECs but can damage the zonules and surrounding tissues. See Nishi, J. Cataract Refract. Surg. 1999 January; 25(1): 106-17 and Nishi et al, Opthalmic Surg. 1991 August; 22(8): 444-50. Other agents that have been tested for the prevention of PCO include RGD peptides to inhibit the migration and proliferation of lens epithelial cells; anti-mitotic drugs, such as Mitomycin C and 5-fluorouracil. See Chung H S, Lim S J, Kim H B. J Cataract Refract Surg. 2000 October; 26(10): 1537-42; Shin D H, Kim Y. Y., Ren J. et al. Ophthalmology. 1998; 105: 1222-1226.
Unfortunately most chemical agents described above, when used at their effective doses, demonstrate unacceptable levels of toxicity to surrounding ocular tissues including ocular cells such as corneal endothelial cells (CEDCs) and retinal pigmented epithelial cells (RPECs).